Circadian systems are programmed by a transcription-translation feedback loop that generates daily cycles of energy storage and utilization in synchrony with the 24 hr rotation of the Earth. In mammals, the core clock is located in the suprachiasmatic nucleus and entrains extra-SCN and peripheral clocks to the light-dark cycle, including peripheral tissues involved in glucose and lipid metabolism. We have used experimental genetic approaches to dissect the mechanisms through which the internal clock network contributes to energy balance and glucose homeostasis with a specific focus on the interplay between peripheral tissue clocks and brain. This approach has demonstrated a primary role of clock genes in endocrine pancreas insulin secretion. In contrast, ablation of the clock in liver and muscle results in altered oxidative metabolism, due to effects on cellular NAD⁺ biogenesis and regulation of NAD⁺-dependent deacetylases within both nucleus and mitochondrion. Surprisingly, we have also found that high-fat feeding causes reciprocal disruption of both brain and peripheral tissue clocks manifest as period lengthening and reduced amplitude of metabolic and circadian gene oscillations. These studies highlight the interdependence of circadian and metabolic processes and uncover a network of molecular interactions that impose temporal regulation on physiological systems.